Fondaparinux Sodium is the first synthetic selective inhibitor of thrombin Xa factor, marketed as an anticoagulant drug in 2001, with a chemical name of methyl O-(2-deoxy-2-sulfamido-6-O-sulfo-α-D-glucopyranosyl)-(1→4)-O-(β-D-glucopyranosyluronic acid)-(-1→4)-O-(2-deoxy-2-sulfamido-3,6-di-O-sulfo-α-D-glucopyranosyl)-(1-4)-O-(2-O-sulfo-α-L-idopyranosyluronic acid)-(1→4)-2-deoxy-2-sulfamido-6-O-sulfo-α-D-glucopyranoside decasodium salt, a molecular weight of 1728, and a chemical structure as shown in formula 8:

The structure of Fondaparinux Sodium has the following characteristics: Fondaparinux Sodium is formed by sequentially connecting five monosaccharide segments different from each other by an α or β glycosidic bond, with the five monosaccharide segments constituting Fondaparinux Sodium represented from right to left by the letters A, B, C, D and E respectively, wherein segments A, C and E are glucosamine derivatives, segment B is an iduronic acid derivative, and segment D is a glucuronic acid derivative. There are free hydroxyl groups, sulfated hydroxyl groups and sulfated amino groups in the structure of Fondaparinux Sodium, and thus the use of suitable protecting groups in its synthesis design must be taken into consideration in order to meet the following requirements: (1) during the reaction of forming the glycosidic bonds, the protecting groups should be advantageous to form the correct glycosidic bonds in terms of regioselectivity and stereoselectivity; (2) the protecting groups should be selected to allow sulfation in the required position, while other hydroxyl groups are not sulfated; (3) as the synthesis route of the compound is very long, the protecting groups should be selected to be advantageous to improve the efficiency of the reaction, in particular the selectivity and the yield of the glycosylation reaction. In the prior art the synthesis steps of Fondaparinux Sodium are long, the operation is complicated and the total yield is low, being not conducive to industrial-scale production.
The DC disaccharide segment is particularly difficult to synthesize in a total synthesis process of Fondaparinux Sodium. The configuration of the glycosidic bond connecting D segment and C segment is a β configuration, but there is a stereoselectivity problem when the glycosylation reaction for connecting D segment and C segment is carried out, and the reaction may generate α and β glycosylation products simultaneously, resulting in a low yield of the reaction as well as difficult separation and purification of the products. In 1984, Sinay et al (Sinay, P.; Jacquinet, J.; Peittou, M.; Duchaussoy, P.; Lederman, I.; Choay, J. Total synthesis of a heparin pentasaccharide fragment having high affinity for antithrombin. III, Carbohydrate Research, 1984, 132, C5-C9) reported the use of a compound of formula 16 and a compound of formula 17 as raw materials in the synthesis of a DC disaccharide segment intermediate compound of formula 18 under the effect of expensive silver salts, wherein the conditions of the glycosylation reaction are harsh, the reaction needs to be carried out for six days, the yield is only 50%, the product is difficult to separate and purify, and the synthesis of the compound of formula 16 as a raw material requires a 14-step chemical reaction; U.S. Pat. No. 4,818,816 also describes the same results.

In 1986, Kreuzer, et al. (Kreuzer, M.; Thiem, J. Aufbau von oligosacchariden mit glycosylfluoriden unter lewissaure-katalyse. Carbohydrate Research, 1986, 149, 347-361) reported the use of a fluorinated glycoside compound of formula 19 and a compound of formula 4 in a glycosylation reaction under the effect of equivalent titanium tetrafluoride to synthesize a DC disaccharide segment intermediate compound of formula 12, wherein the yield is only 66%, and the reaction requires the use of large quantities of expensive and highly toxic fluorine-containing reagents.

In 1991, Duchaussoy et al (Duchaussoy, P.; Lei, P. S.; Petitou, M.; Synay, P.; Lormeau, J. C.; Choay, J. The first total synthesis of the antithrombin III binding site of porcine mucosa heparin. Bioorg. Med. Chem. Lett., 1991, 1, 99-102) reported the use of a compound of formula 20 and a compound of formula 4 in the synthesis of a DC disaccharide segment intermediate compound of formula 21 under the effect of expensive silver salts, wherein the conditions of the glycosylation reaction are harsh, the yield is only 51%, the reaction has a stereoselectivity of α/β ratio of 1/12, and the product is difficult to separate and purify.

In 1991, Petitou et al (Petitou, M.; Jaurand, G.; Derrien, M.; Duchaussoy, P.; Choay, J. A new, highly potent, heparin-like pentasaccharide for fragment containing a glucose residue instead of a glucosamine. Bioorg. Med. Chem. Lett., 1991, 1, 95-98) reported the use of a cellobiose connected by a β-configuration glycosidic bond in the conversion of functional groups and protecting groups to synthesize a disaccharide segment intermediate, but the synthesis route is long, and the total yield is low. U.S. Pat. No. 7,541,445 describes the glycosylation reaction between a derivative of methyl 2-O-benzoyl-glucuronate and the C segment, wherein the glycosylation reaction is controlled by the effect of neighboring group participation of the benzoyl group to build a β-configuration glycosidic bond in the DC disaccharide segment, followed by the conversion of the derivative of methyl 2-O-benzoyl-glucuronate in the disaccharide segment into a derivative of methyl 2-O-benzyl-glucuronate through a three-step chemical reaction, but these conversions add a number of reaction steps and bring more difficulties to industrial production.
In 1995, Budesinsky et al (Budesinsky, M.; Cerny, M.; Cerny, I.; Samek, S.; Trnka, T. Preparation of β-D-glucopyranosyl derivatives of 1,6;2,3- and 1,6;3,4-dianhydro-β-D-hexopyranoses and their 1H and 13C NMR spectra. Collect Czech Chem Commun., 1995, 60, 311-323) reported the use of a brominated glycoside compound of formula 22 and a compound of formula 4 in a glycosylation reaction to synthesize a DC disaccharide segment compound of formula 12, but the reaction requires the use of large quantities of expensive silver salts as an active agent of the glycosylation reaction.

In 1998, Carmelita et al (Kasuya, M. C.; Hatanaka, K.; The chemical synthesis of a cyclic oligosaccharide derivative with branching. Tetrahedron Lett., 1998, 39, 9719-9722) reported the use of a compound of formula 23 and a compound of formula 4 in a glycoside reaction, and since the compound of formula 23 has a benzyl group as a protecting group of the 2-position hydroxy group, the resulting product is a mixture of an α-configuration product, a compound of formula 24 and a β-configuration product, a compound of formula 25 in a ratio of 20:80. The β-configuration product, the compound of formula 25 can be used to synthesize a DC disaccharide segment intermediate, but due to the difficult separation and purification of the above a/(3 mixture, the method is difficult to apply in mass production.

Chinese Invention Patent Application No. CN201180047939.8 document discloses the use of a compound of formula 26 and a compound of formula 4 in a glycosylation reaction to synthesize a DC disaccharide segment intermediate compound of formula 27, but the synthesis route of the compound of formula 26 as a raw material of the reaction is long and requires the use of expensive and highly toxic reagents, and the acetal protecting group in the compound has low stability against the acidic active agent of the glycosylation reaction, resulting in a low yield and a poor reproducibility of the glycosylation reaction.
In summary, the existing synthetic methods of a DC disaccharide intermediate suffer from multi-step reactions, expensive and highly toxic reagents being used, a low yield of the reaction, difficult separation and purification as well as high cost, and bring a lot of difficulties to large-scale manufacture.